Recent advances in stimuli-responsive degradable block copolymer micelles: synthesis and controlled drug delivery applications

(Bio)degradation in response to external stimuli (stimuli-responsive degradation, SRD) is a desired property in constructing novel nanostructured materials. For polymer-based multifunctional drug delivery applications, the degradation enables fast and controlled release of encapsulated therapeutic drugs from delivery vehicles in targeted cells. It also ensures the clearance of the empty device after drugs are delivered to the body. This review summarizes recent development of various strategies to the design and synthesis of self-assembled micellar aggregates based on novel amphiphilic block copolymers having different numbers of stimuli-responsive cleavable elements at various locations. These cleavable linkages including disulfide, acid-labile, and photo-cleavable linkages are incorporated into micelles, and then are cleaved in response to cellular triggers such as reductive reaction, light, and low acid. The well-designed SRD micelles have been explored as controlled/enhanced delivery vehicles of drugs and genes. For future design and development of effective stimuli-responsive degradable micelles toward tumor-targeting delivery applications in vivo, a high degree of control over degradation for tunable release of encapsulated anticancer drugs as well as bioconjugation for active tumor-targeting is required.     

Advances in Targeting Drug Biological Carriers for Enhancing Tumor Therapy Efficacy

Chemotherapy drugs continue to be the main component of oncology treatment research and have been proven to be the main treatment modality in tumor therapy. However, the poor delivery efficiency of cancer therapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. The recent integration of biological carriers and functional agents is expected to camouflage synthetic biomimetic nanoparticles for targeted delivery. The promising candidates, including but not limited to red blood cells and their membranes, platelets, tumor cell membrane, bacteria, immune cell membrane, and hybrid membrane are typical representatives of biological carriers because of their excellent biocompatibility and biodegradability. Biological carriers are widely used to deliver chemotherapy drugs to improve the effectiveness of drug delivery and therapeutic efficacy in vivo, and tremendous progress is made in this field. This review summarizes recent developments in biological vectors as targeted drug delivery systems based on microenvironmental stimuli-responsive release, thus highlighting the potential applications of target drug biological carriers. The review also discusses the possibility of clinical translation, as well as the exploitation trend of these target drug biological carriers.     

Remotely controlled electro-responsive on-demand nanotherapy based on amine-modified graphene oxide for synergistic dual drug delivery

This study focuses on the development of a new electric field responsive graphene oxide (GO) nanoparticle system for on-demand drug delivery. Today, GO is an attractive option adopted in various biological applications for its exclusive features such as flexibility, conductiveness, cost-effectiveness, and external stimuli-responsive nature. It is usual to utilize multiple drugs in cancer treatment. This kind of therapy has lesser side-effects, drug resistance, and is more effective than utilizing only one drug. This study aims to determine low-voltage-controlled dual drug (aspirin and doxorubicin) release from GO surface. Here, we have demonstrated how to control the drug release rate remotely with a handy mobile phone, with zero passive release at idle time. In addition, the study focused to estimate the synergism of aspirin with doxorubicin in the release mechanism from GO in the presence of external voltage, using the spectroscopic method. Moreover, we observed aspirin- and doxorubicin-induced synergistic antitumor activity in MDA-MB 231 (breast cancer cell) in vitro. Thus, our study presents a noble combination of aspirin and doxorubicin that could be utilized for remotely controlled on-demand drug delivery for triple negative breast cancer treatment, using GO as a carrier.     

Applications of bacterial cellulose in food,cosmetics and drug delivery

Bacterial cellulose (BC) is a versatile biopolymer with better material properties, such as purity, high degree of porosity, relative high permeability to liquid and gases, high water-uptake capacity, tensile strength and ultrafine network. This review explores the applications of BC and its hydrogels in the fields of food, cosmetics and drug delivery. Applications of BC in foods are ranging from traditional dessert, low cholesterol diet, vegetarian meat, and as food additive and dietary aid to novel applications, such as immobilization of enzymes and cells. Applications in cosmetics include facial mask, facial scrub, personal cleansing formulations and contact lenses. BC for controlled drug delivery, transdermal drug delivery, dental drug delivery, protein delivery, tissue engineering drug delivery, macromolecular prodrug delivery and molecularly imprinted polymer based enantioselective drug delivery are also discussed in this review. The applications of BC in food and cosmetics provide the basis for BC-based functional foods, nutraceuticals, cosmeceuticals and medicated cosmetics. On the basis of current studies, the BC-based drug delivery could be further fine-tuned to get more sophisticated control on stimuli-responsive drug release. Along with the currently available literature, further experiments are required to obtain a blueprint of drug in vivo performance, bioavailability and in vitro–in vivo correlation.     

Functionalized mesoporous silica materials for controlled drug delivery

In the past decade, non-invasive and biocompatible mesoporous silica materials as efficient drug delivery systems have attracted special attention. Great progress in structure control and functionalization (magnetism and luminescence) design has been achieved for biotechnological and biomedical applications. This review highlights the most recent research progress on silica-based controlled drug delivery systems, including: (i) pure mesoporous silica sustained-release systems, (ii) magnetism and/or luminescence functionalized mesoporous silica systems which integrate targeting and tracking abilities of drug molecules, and (iii) stimuli-responsive controlled release systems which are able to respond to environmental changes, such as pH, redox potential, temperature, photoirradiation, and biomolecules. Although encouraging and potential developments have been achieved, design and mass production of novel multifunctional carriers, some practical biological application, such as biodistribution, the acute and chronic toxicities, long-term stability, circulation properties and targeting efficacy in vivo are still challenging.     

Cucurbit[<Emphasis Type="Italic">n</Emphasis>]uril-based host–guest-metal ion chemistry: an emerging branch in cucurbit[<Emphasis Type="Italic">n</Emphasis>]uril chemistry

The unique pumpkin-shape macrocyclic structure with inherent cavities renders cucurbituril (CB) a type of versatile supramolecular container. On account of their good biocompatibility and low toxicity, the applications of CB to encapsulate drug molecules provide promising candidates and the pharmacological activities have been investigated currently. How to control over the uptake and release of the guest at will is significant for practical applications of drug delivery. The noncovalent nature of supramolecular interactions offers variety of options to control the release of guest molecules from CB under external stimuli, including pH, temperature, metal cations, competing guests, light, redox and so on. Moreover, CB containers are capable of assembling into higher ordered supramolecular structures such as polymers, nanoparticles, hydrogels, and colloids, which greatly enrich the scope of CB-type inclusion materials. Those results provide useful principles and guidelines for controlled release from supramolecular containers.     

Redox-Sensitive Stomatocyte Nanomotors: Destruction and Drug Release in the Presence of Glutathione

The development of artificial nanomotor systems that are stimuli-responsive is still posing many challenges. Herein, we demonstrate the self-assembly of a redox-responsive stomatocyte nanomotor system, which can be used for triggered drug release under biological reducing conditions. The redox sensitivity was introduced by incorporating a disulfide bridge between the hydrophilic poly(ethylene glycol) block and the hydrophobic polystyrene block. When incubated with the endogenous reducing agent glutathione at a concentration comparable to that within cells, the external PEG shells of these stimuli-responsive nanomotors are cleaved. The specific bowl-shaped stomatocytes aggregate after the treatment with glutathione, leading to the loss of motion and triggered drug release. These novel redox-responsive nanomotors can not only be used for remote transport but also for drug delivery, which is promising for future biomedical applications.     

Nanostructured polymer assemblies formed at interfaces: applications from immobilization and encapsulation to stimuli-responsive release

In recent years, interfacial properties have been tailored with nanostructured polymer assemblies to generate materials with specific properties and functions for application in diverse fields, including biomaterials, drug delivery, catalysis, sensing, optics and corrosion. This perspective begins with a brief introduction of the assembly techniques that are commonly employed for the synthesis of nanostructured polymer materials, followed by discussions on how the interfaces influence the properties and thus the functionalities of the polymer materials prepared. Applications of the interfacial polymer nanostructures, particularly for the immobilization and encapsulation of cargo, are then reviewed, focusing on stimuli-responsive cargo release from the polymer nanostructured assemblies for controlled delivery applications. Finally, future research directions in these areas are briefly discussed.     

Biomedical application of responsive ‘smart’ electrospun nanofibers in drug delivery system: A minireview

Electrospinning is a versatile method for producing continuous nanofibers. It has since become an easy and cost-effective technique in the manufacturing process and drawn keen interests in most biomedical field applications. Nanofibers have garnered great attention in nanomedicine due to their resemblance with the extracellular matrix (ECM). Like nanoparticles, its unique characteristics of higher surface-to-volume ratio and the tunability of the polymers utilizing nanofiber have increased the efficiency in encapsulation and drug-loading capabilities. Smart or “stimuli-responsive” polymers have shown particular fascination in controlled release, where their ability to react to minor changes in the environment, such as temperature, pH, electric field, light, or magnetic field, distinguishes them as intelligent. Polymers are a popular material for the design of drug delivery carriers; consequently, various types of drugs, including antiviral, proteins, antibiotics, DNA and RNA, are successfully encapsulated in the pH-dependent nanofibers with smart polymers which is a polymer that can respond to change such as pH change, temperature. In this minireview, we discuss applications of smart electrospun pH-responsive nanofibers in the emerging biomedical developments which includes cancer drug targeting, oral controlled release, wound healing and vaginal drug delivery.     

An Antitumor Dual-Responsive Host-Guest Supramolecular Polymer Based on Hypoxia-Cleavable Azocalix[4]arene

The exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli-responsive supramolecular polymers (SPs) based on host–guest interactions. Most functional guests, however, fail to manifest stimuli-responses. Herein, a hypoxia-responsive dimeric azocalixarene (D-SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli-responsive SPs. Since azocalixarenes can also be compatible with stimuli-responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide-containing linker to afford a glutathione (GSH)-responsive ditropic guest (D-CPT). A unique dual-responsive SP was obtained by 1 : 1 mixing of D-SAC4A and D-CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT-release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor-suppressive effects of DSPNs.     

由聚合物门控的介孔二氧化硅基刺激响应性药物递送系统

本文主要介绍了以聚合物体系作为门控构筑的基于介孔二氧化硅纳米粒子的刺激响应性药物控释体系, 并根据聚合物类别将门控体系分为聚合物刷、 聚合物交联网络和聚合物包裹层三类. 根据聚合物“阀门”与无机纳米粒子的共价或非共价连接方式, 综述了这些杂化材料在不同外界刺激作用下的药物控制释放行为, 并给出该领域所面临的机遇和挑战.     

活性氧刺激响应纳米载体

纳米载体一般是由天然高分子或人工合成高分子组成的、纳米级范畴的运输系统,具有减少药物毒性、提高药物的靶向性、增加药物有效性等优点。随着生物医学技术的进步,有研究表明,作为氧化代谢产物的活性氧(ROS)在疾病部位常常伴随着过表达的异常现象。基于此,近年来ROS刺激响应纳米载体获得了关注和发展,以不同响应机制的ROS响应基团为基础,发展了一系列的ROS响应纳米载体,实现了疾病部位ROS刺激下的药物特异性可控释放。该文聚焦于近年来常用于纳米载体的ROS响应基团,依据元素划分为两大类:硫族元素类响应基团(硫醚、缩硫酮、硒化物、二硒化物、碲化物)和其他元素类响应基团(芳香硼酸酯、过氧草酸酯、二茂铁);通过不同的设计理念将其引入纳米载体,根据ROS响应纳米载体的不同响应机制(疏水-亲水相变、断裂),探讨了载体各自的ROS响应情况、体外药物释放情况,以及在活体中的应用情况。     

Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials

In recent years, intelligent hydrogels which can change their swelling behavior and other properties in response to environmental stimuli such as temperature, pH, solvent composition and electric fields, have attracted great interest. The hydrogels based on polysaccharides incorporated with thermo-responsive polymers have shown unique properties such as biocompatibility, biodegradability, and biological functions in addition to the stimuli-responsive characters. These "smart" hydrogels exhibit single or multiple stimuli-responsive characters which could be used in biomedical applications, including controlled drug delivery, bioengineering or tissue engineering. This review focuses on the recent developments and future trends dealing with stimuli-responsive hydrogels based on grafting/blending of polysaccharides such as chitosan, alginate, cellulose, dextran and their derivatives with thermo-sensitive polymers. This review also screens the current applications of these hydrogels in the fields of drug delivery, tissue engineering and wound healing.     

环糊精超分子聚合物在药物/基因递送载体领域的研究进展

超分子聚合物通常以非共价键作为构筑驱动力,其结构具有动态可逆的特点,在新型响应性聚合物材料中具有突出优势。环糊精可通过主客体识别作用与客体分子如二茂铁、偶氮苯、金刚烷、苯环等形成包合,以此构筑的超分子组装体展现出丰富的自组装-解组装特性、刺激响应性、较低的细胞毒性和较好的生物相容性,有望在药物/基因载体领域得到应用。本文从环糊精超分子聚合物的生物医用出发,着重对近年来环糊精超分子聚合物载体在药物控制释放、基因转染以及药物/基因共递送三方面的研究进展进行了总结和评述,并在此基础上展望了环糊精超分子聚合物的研究方向和发展趋势。     

Construction of Smart Stimuli-Responsive DNA Nanostructures for Biomedical Applications

DNA nanostructures have recently attracted increasing interest in biological and biomedical applications by virtue of their unique properties, such as structural programmability, multi-functionality, stimuli-responsive behaviors, and excellent biocompatibility. In particular, the intelligent responsiveness of smart DNA nanostructures to specific stimuli has facilitated their extensive development in the field of high-performance biosensing and controllable drug delivery. This minireview begins with different self-assembly strategies for the construction of various DNA nanostructures, followed by the introduction of a variety of stimuli-responsive functional DNA nanostructures for assembling metastable soft materials and for facilitating amplified biosensing. The recent achievements of smart DNA nanostructures for controllable drug delivery are highlighted. Finally, the current challenges and possible developments of this promising research are discussed in the fields of intelligent nanomedicine.     

Physicochemical aspects of drug delivery and release from polymer-based colloids

Recent advances in the preparation/loading, surface properties, and applications of polymer-based colloidal drug delivery and release systems, such as block copolymer micelles, polymer nano- and microparticles, polymer-modified liposomes, and chemical and physical hydrogels are presented. Drug release from polymer-based systems is affected by the drug–polymer interactions as well as the polymer microstructure and dissociation/erosion properties. Surface modification with poly(ethylene oxide) has become common in improving the biocompatibility and biodistribution of drug delivery carriers. Site-specific drug delivery can be achieved by polymer-based colloidal drug carriers when ligands of targeting information are attached on the carrier surface or when a phase transition is induced by an external stimulus. While significant progress in being made, many challenges remain in preserving the biological activity and attaining the desired drug release properties, especially for protein and DNA drugs.     

Engineering Flexible Metal-Phenolic Networks with Guest Responsiveness via Intermolecular Interactions

Flexible metal-organic materials are of growing interest owing to their ability to undergo reversible structural transformations under external stimuli. Here, we report flexible metal-phenolic networks (MPNs) featuring stimuli-responsive behavior to diverse solute guests. The competitive coordination of metal ions to phenolic ligands of multiple coordination sites and solute guests (e.g., glucose) primarily determines the responsive behavior of the MPNs, as revealed experimentally and computationally. Glucose molecules can be embedded into the dynamic MPNs upon mixing, leading to the reconfiguration of the metal-organic networks and thus changes in their physicochemical properties for targeting applications. This study expands the library of stimuli-responsive flexible metal-organic materials and the understanding of intermolecular interactions between metal-organic materials and solute guests, which is essential for the rational design of responsive materials for various applications.     

pH‐Responsive Drug‐Delivery Systems

In many biomedical applications, drugs need to be delivered in response to the pH value in the body. In fact, it is desirable if the drugs can be administered in a controlled manner that precisely matches physiological needs at targeted sites and at predetermined release rates for predefined periods of time. Different organs, tissues, and cellular compartments have different pH values, which makes the pH value a suitable stimulus for controlled drug release. pH‐Responsive drug‐delivery systems have attracted more and more interest as “smart” drug‐delivery systems for overcoming the shortcomings of conventional drug formulations because they are able to deliver drugs in a controlled manner at a specific site and time, which results in high therapeutic efficacy. This focus review is not intended to offer a comprehensive review on the research devoted to pH‐responsive drug‐delivery systems; instead, it presents some recent progress obtained for pH‐responsive drug‐delivery systems and future perspectives. There are a large number of publications available on this topic, but only a selection of examples will be discussed.     

聚合物纳米药物载体的研究进展

近年来, 大量研究结果表明纳米技术可显著提高传统药物的疾病治疗效果, 并在生物医学领域引起了广泛关注. 迄今, 多种聚合物纳米体系已被研发并用于药物的靶向递送. 随着纳米技术的不断发展, 各类生物微环境响应的功能基团也被应用于构筑新型药物载体, 以提高患病部位的药物富集及减少药物的毒副作用. 聚合物纳米药物载体在癌症治疗、 代谢类疾病治疗及抗菌等方面展现出巨大潜力. 本文系统评述了聚合物纳米药物载体的最新研究进展及在生物医药方面的应用.